CODAS syndrome is a multi-system developmental disorder characterized by intellectual disability, cataracts, and abnormalities in dentition, hearig and skeletal structure. CODAS is an acronym for cerebral, ocular, dental, auricular and skeletal anomalies. Using whole exome analysis and direct genomic sequencing, we recently demonstrated that mutations in the LONP1 gene are associated with CODAS syndrome. LONP1 encodes mitochondrial Lon, which is an ATP-dependent protease, a chaperone and a DNA-binding protein. Lon binds directly to DNA and RNA, and is required for the maintenance and expression of mitochondrial DNA (mtDNA). As mtDNA encodes essential subunits of the oxidative phosphorylation system, changes in Lon function at the mitochondrial genome will impact cellular energetics and cell survival. Our published and unpublished findings demonstrate that the majority of LonCODAS mutations cluster within the AAA+ domain of Lon, which mediates DNA- and RNA- binding as well as ATP hydrolysis. This project focuses on the direct and specific role of Lon in mitochondrial gene expression (i.e. transcription and translation). The results obtained will provide key mechanistic insights into how Lon dysfunction in these processes contributes to the pathophysiology of CODAS syndrome. In addition, the discovery that CODAS syndrome is linked to naturally occurring mutations in mitochondrial Lon, provides a unique and powerful opportunity to elucidate the diverse functions of this multi-functional enzyme in both human health and common disease processes such as neurodegeneration, oncogenesis, cardiac disease as well as aging.